Diffusion tensor imaging (DTI) has proven to be an important tool for investigating white matter changes associated with many central nervous system (CNS) diseases [Sullivan and Pfefferbaum, 2003;Salat et al., 2005;Assaf and Pasternak, 2008]. Recently, a new diffusion MRI imaging method called Diffusional Kurtosis Imaging (DKI) [Jensen and Helpern, 2003;Jensen et al., 2005;Lu et al., 2006] has been developed. DKI is capable of quantifying the non-Gaussian behavior of water diffusion. Recent DKI studies have demonstrated that mean kurtosis (MK) yields useful and distinct information from that provided by conventional DTI in detecting changes in brain microstructure associated with neurological diseases. [Falangola et al., 2008;Helpern et al., 2007;Ramani et al., 2007]. However, at this point in time, no histological correlation has been performed in the few published DKI animal studies [Falangola et al., 2007, Cheung et al., 2008a;Cheung et al., 2008b] and the quantitative interpretation of DKI metrics remains to be validated. The overall goal of this project is to validate and understand what these new MRI indices of diffusion, mainly the DKI measurements of Mean Kurtosis, axial (K//) and radial (K4) kurtosis, reflect at the tissue level by investigating the relationship between these measurements and axonal and myelin damage in a model of demyelination and remyelination, the cuprizone mouse model. This goal will be achieved by comparing indices of DK metrics and conventional DTI metrics with histological markers of myelin loss, axonal damage and glial cells accumulation during the process of demyelination and remyelination that occur in the corpus callosum of the cuprizone mouse model PUBLIC HEALTH RELEVANCE: The questions addressed in this proposal are whether a new Magnetic Resonance Imaging (MRI) diffusion technique, called Diffusional Kurtosis Imaging (DKI), can be accurate and suitable for quantitative evaluation of brain microstructure changes. As with any new MR technique, the validation and understanding of what the proposed MRI indices reflect at the tissue level is essential for characterizing the normal morphological aspects and the underlying pathology on a disease set. For this validation we will use the cuprizone mouse model of demyelination and remyelination. The significance of this project is to try to validate and understand what these new MRI indices of diffusion reflect at the brain morphological level.